Inflammation is a mechanism that protects mammals from invading pathogens. However, while transient inflammation is necessary to protect a mammal from infection, uncontrolled inflammation causes tissue damage and is the underlying cause of many illnesses. Inflammation is typically initiated by binding of an antigen to T-cell antigen receptor. Antigen binding by a T-cell initiates calcium influx into the cell via calcium ion channels, such as Ca2+-release-activated Ca2+ channels (CRAC). Calcium ion influx in turn initiates a signaling cascade that leads to activation of these cells and an inflammatory response characterized by cytokine production.
Interleukin 2 (IL-2) is a cytokine that is secreted by T cells in response to calcium ion influx into the cell. IL-2 modulates immunological effects on many cells of the immune system. For example, it is a potent T cell mitogen that is required for T cell proliferation, promoting their progression from G1 to S phase of the cell cycle; it stimulates the growth of NK cells; and it acts as a growth factor to B cells and stimulates antibody synthesis.
IL-2, although useful in the immune response, can cause a variety of problems. IL-2 damages the blood-brain barrier and the endothelium of brain vessels. These effects may be the underlying causes of neuropsychiatric side effects observed under IL-2 therapy, e.g. fatigue, disorientation and depression. It also alters the electrophysiological behaviour of neurons.
Due to its effects on both T and B cells, IL-2 is a major central regulator of immune responses. It plays a role in inflammatory reactions, tumour surveillance, and hematopoiesis. It also affects the production of other cytokines, inducing IL-1, TNF-α and TNF-β secretion, as well as stimulating the synthesis of IFN-γ in peripheral leukocytes.
T cells that are unable to produce IL-2 become inactive (anergic). This renders them potentially inert to any antigenic stimulation they might receive in the future. As a result, agents which inhibit IL-2 production can be used for immunosuppression or to treat or prevent inflammation and immune disorders. This approach has been clinically validated with immunosuppressive drugs such as cyclosporin, FK506, and RS61443. Despite this proof of concept, agents that inhibit IL-2 production remain far from ideal. Among other problems, efficacy limitations and unwanted side effects (including dose-dependant nephrotoxicity and hypertension) hinder their use.
Over production of proinflammatory cytokines other than IL-2 has also been implicated in many autoimmune diseases. For example, Interleukin 5 (IL-5), a cytokine that increases the production of eosinophils, is increased in asthma. Overproduction of IL-5 is associated with accumulation of eosinophils in the asthmatic bronchial mucosa, a hall mark of allergic inflammation. Thus, patients with asthma and other inflammatory disorders involving the accumulation of eosinophils would benefit from the development of new drugs that inhibit the production of IL-5.
Interleukin 4 (IL-4) and interleukin 13 (IL-13) have been identified as mediators of the hypercontractility of smooth muscle found in inflammatory bowel disease and asthma. Thus, patients with asthma and inflammatory bowel disease would benefit from the development of new drugs that inhibit IL-4 and IL-13 production.
Granulocyte macrophage-colony stimulating factor (GM-CSF) is a regulator of maturation of granulocyte and macrophage lineage population and has been implicated as a key factor in inflammatory and autoimmune diseases. Anti-GM-CSF antibody blockade has been shown to ameliorate autoimmune disease. Thus, development of new drugs that inhibit the production of GM-CSF would be beneficial to patients with an inflammatory or autoimmune disease.
There is a continuing need for new drugs which overcome one or more of the shortcomings of drugs currently used for immunosuppression or in the treatment or prevention of inflammatory disorders, allergic disorders and autoimmune disorders. Desirable properties of new drugs include efficacy against diseases or disorders that are currently unbeatable or poorly treatable, new mechanism of action, oral bioavailability and/or reduced side effects.
This invention meets the above-mentioned needs by providing certain pyrazinyl and pyridazinyl derivatives that inhibit the activity of CRAC ion channels and inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, and IFNγ. These compounds are particularly useful for immunosuppression and/or to treat or prevent inflammatory conditions, allergic disorders and immune disorders.
In one embodiment, the invention relates to compounds of formula (I):
                or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:        L is a linker selected from the group consisting of —NRCH2—, —CH2NR—, —C(O)—, —NR—C(O), —C(O)—NR—, —C(S)—, —NR—C(S)—, —C(S)—NR—;        each Z is independently selected from the group consisting of a lower alkyl, a lower haloalkyl, a halo, a lower alkoxy, a lower alkyl sufanyl, cyano, nitro, or lower haloalkoxy;        R, for each occurrence is independently selected from —H, an alkyl, —C(O)R5, or —C(O)OR5;        R1 is an optionally substituted aryl or an optionally substituted heteroaryl;        R2 is an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl or an optionally substituted heteroaryl;        R5, for each occurrence, is independently, H, an alkyl, a cycloalkyl, a heterocyclyl, an aryl, a heteroaryl, an aralkyl, or a heteraralkyl; and        n is 0, 1 or 2.        
In another embodiment, the invention relates to compounds of formula (V):
                or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:        R12 is an aryl or a heteroaryl, wherein the aryl and heteroaryl are optionally substituted with one or more substituent selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a halo, cyano, nitro, —OR17, —SR17, —S(O)pR17, —S(O)pOR17, —OS(O)pR17, —OS(O)pOR17, —NR17S(O)pR17, —S(O)pNR15R16, —NR15R16, —C(X3)R17, —C(X3)OR17, —C(X3)SR17, —C(X3)NR15R16, —NR17C(X3)R18, —NR17C(X3)OR18, —NR17C(X3)SR18, —NR17C(X3)NR15R16, —OC(X3)R17, —OC(X3)OR17, —OC(X3)SR17, —SC(X3)OR17, —SC(X3)SR17, —OC(X3)NR15R16, —SC(X3)NR15R16, —P(X4)(X5R17)2, —X5P(X4)(X5R17)2, —P(X4)(R17)2, —P(X4)(R17)(X5R17);        R13 is a cycloalkyl, a cycloalkenyl, an aryl, or a heteroaryl, wherein the cycloalkyl, cycloalkenyl, aryl, or heteroaryl are optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl, a halo, cyano, nitro, a haloalkyl, —OR17, —SR17, —S(O)pR17, —S(O)pOR17, —OS(O)pR17, —OS(O)pOR17, —S(O)pNR15R16, —NR15R16, —C(X3)R17, —C(X3)OR17, —C(X3)SR17, —C(X3)NR15R16, —NR17C(X3)R18, —NR17C(X3)OR18, —NR17C(X3)SR18, —NR17C(X3)NR15R16, —OC(X3)R17, —OC(X3)OR17, —OC(X3)SR17, —SC(X3)OR17, —SC(X3)SR17, —OC(X3)NR15R16; —SC(X3)NR15R16, —P(X4)(X5R17)2, —X5P(X4)(X5R17)2; —P(X3)(R17)2, —P(X4)(R17)(X5R17);        R14, for each occurrence is independently selected from —H, an alkyl, —C(O)R20, or —C(O)OR20;        R15 and R16, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl; or R15 and R16 taken together with the nitrogen to which they are attached are an optionally substituted heterocyclyl or optionally substituted heteroaryl;        R17 and R18, for each occurrence are, independently, H, an optionally substituted alkyl, an optionally substituted alkenyl, an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted heterocyclyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, or an optionally substituted heteraralkyl;        R19, for each occurrence, is independently —H, a halo, an alkyl, —OR17, —NR15R16, —C(O)R17, —C(O)OR17, or —C(O)NR15R16;        R20, for each occurrence, is independently, H or an alkyl;        X3 is ═O, ═S, or ═N—R19;        X4 is ═O or ═S;        X5 is —O— or —S—;        p is 1 or 2; and        Z and n are defined as for formula (I).        
In another embodiment, the invention relates to compounds of formula (VI):
                or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:        R, R1, R2, Z and n are defined as for formula (I).        
In another embodiment, the invention relates to compounds of formula (IX):
                or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:        R21 is an alkyl which is optionally substituted with one or more substituents selected from the group consisting of an optionally substituted alkynyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted aralkyl, an optionally substituted heteraralkyl, a halo, cyano, nitro, a haloalkyl, —OR17, —SR17, —S(O)pR17, —S(O)pOR17, —OS(O)pR17, —OS(O)pOR17, —S(O)pNR15R16, —NR15R16, —C(X3)OR17, —C(X3)OR17, —C(X3)SR17, —C(X3)NR15R16, —NR17C(X3)R18, —NR17C(X3)OR18, —NR17C(X3)SR18, —NR17C(X3)NR15R16, —OC(X3)R17, —OC(X3OR17, —OC(X3)SR17, —SC(X3)OR17, —SC(X3)R17, —OC(X3)NR15R16, —SC(X3)NR15R16, —P(X4)(X5R17)2, —X5P(X4R17)2, —P(X4)(R17)2, —P(X4)(X5R17);        R1, Z and n are defined as for formula (I); and        R15, R16, R17, R18, X3, X4, X5, and p are defined as for formula (V).        
In another embodiment, the invention relates to compounds of formula (XII):
                or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, wherein:        X8 and X9 are N and X10 and X11 are CH or CZ; or X10 and X11 are N and X8 and X9 are CH or CZ;        L, Z, R1, and R2 are defined as for formula (I).        
A compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof is particularly useful inhibiting immune cell (e.g., T-cells and/or B-cells) activation (e.g., activation in response to an antigen). In particular, a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof can inhibit the production of certain cytokines that regulate immune cell activation. For example, a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof can inhibit the production of IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, INF-γ or combinations thereof. Moreover, a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof can modulate the activity of one or more ion channel involved in activation of immune cells, such as CRAC ion channels.
In one embodiment, compounds of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof are particularly useful for inhibiting mast cell degranulation. Mast cell degranulation has been implicated in allergic reactions.
A compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof is particularly useful for immunosuppression or for treating or preventing inflammatory conditions, allergic disorders, and immune disorders.
The invention also encompasses pharmaceutical compositions comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof; and a pharmaceutically acceptable carrier or vehicle. These compositions may further comprise additional agents. These compositions are useful for immunosuppression and treating or preventing inflammatory conditions, allergic disorders and immune disorders.
The invention further encompasses methods for treating or preventing inflammatory conditions, allergic disorders, and immune disorders, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. These methods may also comprise administering to the subject an additional agent separately or in a combination composition with the compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
The invention further encompasses methods for suppressing the immune system of a subject, comprising administering to a subject in need thereof an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof, or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof. These methods may also comprise administering to the subject an additional agent separately or in a combination composition with the compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
The invention further encompasses methods for inhibiting immune cell activation, including inhibiting proliferation of T cells and/or B cells, in vivo or in vitro comprising administering to the cell an effective amount of a compound of the invention or a pharmaceutically acceptable salt solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
The invention further encompasses methods for inhibiting cytokine production in a cell (e.g., IL-2, IL-4, IL-5, IL-13, GM-CSF, TNF-α, and/or INF-γ production) in vivo or in vitro comprising administering to a cell an effective amount of a compound of the invention or a pharmaceutically acceptable, salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
The invention further encompasses methods for modulating ion channel activity (e.g., CRAC) in vivo or in vitro comprising administering an effective amount of a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof or a pharmaceutical composition comprising a compound of the invention or a pharmaceutically acceptable salt, solvate, clathrate, or prodrug thereof.
All of the methods of this invention may be practice with a compound of the invention alone, or in combination with other agents, such as other immunosuppressive agents, anti-inflammatory agents, agents for the treatment of allergic disorders or agents for the treatment of immune disorders.